Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity

• Published in: International Journal of Obesity Vol. 39; no. 8; pp. 1274 - 1281
• Main Authors: Muralimanoharan, S, Guo, C, Myatt, L, Maloyan, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2015; Nature Publishing Group
• Subjects: 38/1; 42/109; 42/89; 631/443/319/333/1465; 82/29; 82/80; 96/106; 96/21; Adult; Blotting, Western; Body mass index; Body size; Body weight; Cell Hypoxia; Cesarean section; Childbirth & labor; Chromatin; Complications and side effects; Development and progression; Diabetes; Dimorphism (Biology); Epidemiology; Female; Females; Fetal Development; Fetuses; Gene expression; Genes; Genetic aspects; Gynecology; Health aspects; Health Promotion and Disease Prevention; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunity, Innate; Immunoprecipitation; Inflammation; Inflammation - immunology; Inflammation - metabolism; Internal Medicine; Intrauterine exposure; Medicine; Medicine & Public Health; Metabolic Diseases; MicroRNA; MicroRNAs; MicroRNAs - metabolism; miRNA; Mitochondria; Mitochondrial diseases; Necrosis; NF-kappa B - metabolism; NF-κB protein; Obesity; Obesity - complications; Obesity - metabolism; Obesity - physiopathology; Obstetrics; original-article; Overweight; Physiological aspects; Placenta; Placenta - immunology; Placenta - metabolism; Placental diseases; Pre-eclampsia; Preeclampsia; Pregnancy; Pregnancy complications; Pregnancy Complications - metabolism; Pregnancy Complications - physiopathology; Pregnant Women; Pretreatment; Protein Transport; Public Health; Respiration; Reverse transcription; Ribonucleic acid; RNA; Sex; Sex Characteristics; Sex differences; Sexual dimorphism; siRNA; Term Birth; Tumor necrosis factor-α; Women; Womens health; United States; United States > US
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2015.45

Background:
Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal–fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called ‘hypoxamir’ regulated by HIF-1α, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity.
Methods:
Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25–24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription–PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation.
Results:
Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1α in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFα) were increased in OW and OB placentas of females but not males, and
in silico
analysis suggested that activation of miR-210 expression in these placentas might be activated by NFκB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFα showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFα-mediated inhibition of mitochondrial respiration.
Conclusions:
Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFκB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses.